tbuckley/cabot-search huggingface dataset:
A novel regulatory facet for hypertriglyceridemia: The role of microRNAs in the regulation of triglyceride-rich lipoprotein biosynthesis
Authors: Masoumeh Khalifeh, Raul D. Santos, Reza Kazemi Oskuee, Ali Badiee, Seyed Hamid Aghaee-Bakhtiari, Amirhossein Sahebkar
Journal: Progress in Lipid Research (2022)
Brown adipose tissue-derived Nrg4 alleviates endothelial inflammation and atherosclerosis in male mice
Authors: Lingfeng Shi, Yixiang Li, Xiaoli Xu, Yangyang Cheng, Biying Meng, Jinling Xu, Lin Xiang, Jiajia Zhang, Kaiyue He, Jiayue Tong, Junxia Zhang, Lingwei Xiang, Guangda Xiang
Journal: Nature Metabolism (2022)

Abstract Brown adipose tissue (BAT) activity contributes to cardiovascular health by its energy-dissipating capacity but how BAT modulates vascular function and atherosclerosis through endocrine mechanisms remains poorly understood. Here we show that BAT-derived neuregulin-4 (Nrg4) ameliorates atherosclerosis in mice. BAT-specific Nrg4 deficiency accelerates vascular inflammation and adhesion responses, endothelial dysfunction and apoptosis and atherosclerosis in male mice. BAT-specific Nrg4 restoration alleviates vascular inflammation and adhesion responses, attenuates leukocyte homing and reduces endothelial injury and atherosclerosis in male mice. In endothelial cells, Nrg4 decreases apoptosis, inflammation and adhesion responses induced by oxidized low-density lipoprotein. Mechanistically, protein kinase B (Akt)–nuclear factor-κB signaling is involved in the beneficial effects of Nrg4 on the endothelium. Taken together, the results reveal Nrg4 as a potential cross-talk factor between BAT and arteries that may serve as a target for atherosclerosis.
Three-Year Update of Tisagenlecleucel in Pediatric and Young Adult Patients With Relapsed/Refractory Acute Lymphoblastic Leukemia in the ELIANA Trial
Authors: Theodore W. Laetsch, Shannon L. Maude, Susana Rives, Hidefumi Hiramatsu, Henrique Bittencourt, Peter Bader, André Baruchel, Michael Boyer, Barbara De Moerloose, Muna Qayed, Jochen Buechner, Michael A. Pulsipher, Gary Douglas Myers, Heather E. Stefanski, Paul L. Martin, Eneida Nemecek, Christina Peters, Gregory Yanik, Seong Lin Khaw, Kara L. Davis, Joerg Krueger, Adriana Balduzzi, Nicolas Boissel, Ranjan Tiwari, Darragh O'Donovan, Stephan A. Grupp
Journal: Journal of Clinical Oncology (2022)

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. In the primary analysis of the global phase II ELIANA trial (ClinicalTrials.gov identifier: NCT02435849), tisagenlecleucel provided an overall remission rate of 81% in pediatric and young adult patients with relapsed or refractory B-cell acute lymphoblastic leukemia (R/R B-ALL), with 59% of responders remaining relapse-free at 12 months. Here, we report an update on efficacy, safety, and patient-reported quality of life in 79 pediatric and young adult patients with R/R B-ALL following a median follow-up of 38.8 months. The overall remission rate was 82%. The median event-free survival was 24 months, and the median overall survival was not reached. Event-free survival was 44% (95% CI, 31 to 57) and overall survival was 63% (95% CI, 51 to 73) at 3 years overall (most events occur within the first 2 years). The estimated 3-year relapse-free survival with and without censoring for subsequent therapy was 52% (95% CI, 37 to 66) and 48% (95% CI, 34 to 60), respectively. No new or unexpected long-term adverse events were reported. Grade 3/4 adverse events were reported in 29% of patients > 1 year after infusion; grade 3/4 infection rate did not increase > 1 year after infusion. Patients reported improvements in quality of life up to 36 months after infusion. These findings demonstrate favorable long-term safety and suggest tisagenlecleucel as a curative treatment option for heavily pretreated pediatric and young adult patients with R/R B-ALL.
Boosting B Cell and Macrophage‐Mediated Humoral Immunity with Fusion Nanovesicles for Triple‐Negative Breast Cancer Combined Therapy
Authors: Yulin Yu, Yang Li, Yinmei Tian, Qian Hu, Xiaonan Li, Jingyao Tu, Han Liu, Conglian Yang, Li Kong, Zhiping Zhang
Journal: Advanced Healthcare Materials (2022)

Abstract Cell‐derived nanovesicles are widely utilized as therapeutic agents for cancer therapy. Current research mostly focuses on their ability to activate antitumor cellular immunity. However, whether they can activate and participate in antitumor humoral immunity is rarely studied. Here, doxorubicin‐loaded hybrid cell nanovesicles (DNVs) are designed for boosting antitumor humoral and cellular immunity. The hybrid cell nanovesicles are generated through fusion of nanovesicles derived from M1‐type macrophages and 4T1 tumor cells. It is found that DNVs can accumulate at tumor tissues and draining lymph nodes effectively, which results in the activation of antitumor immune response and significant inhibition of tumor progression. During this process, dendritic cells are effectively activated, subsequently inducing cytotoxicity T lymphocytes‐mediated cellular immunity. Furthermore, DNVs elicit the antitumor humoral immunity through boosting T follicular helper cells and germinal center B cells. By analyzing the mechanism behind humoral immunity activation, it is found that M1‐type macrophages repolarized by DNVs play an important role. In general, besides antitumor cellular immunity, the proposed hybrid nanovesicles provide a promising strategy for enhancing antitumor humoral immunity by macrophages repolarization and germinal center B cells activation.
Rhythm Mild‐Temperature Photothermal Therapy Enhancing Immunogenic Cell Death Response in Oral Squamous Cell Carcinoma
Authors: Jianchuan Ran, Tao Liu, Chuanhui Song, Zheng Wei, Chuanchao Tang, Zichen Cao, Huihui Zou, Xinyu Zhang, Yu Cai, Wei Han
Journal: Advanced Healthcare Materials (2022)

Abstract The low antitumor efficiency and unexpected thermo‐tolerance activation of mild‐temperature photothermal therapy (mPTT) severely impede the therapeutic efficacy, thereby the implementation of reasonable mPTT procedure to improve antitumor efficiency is of great significance for clinical transformation. Herein, a rhythm mPTT with organic photothermal nanoparticles (PBDB‐T NPs) is demonstrated, synergistically increasing tumor elimination and intense immunogenic cancer cell death (ICD) to elicit tumor‐specific immune responses for tumor treatment. Specifically, PBDB‐T NPs are characterized by favorable biocompatibility, excellent and controllable photothermal properties, exhibit the properties of noninvasive diagnostic imaging, and effective mPTT against oral squamous cell carcinoma (OSCC). Encouragingly, a temperature‐dependent release of damage‐associated molecular patterns (DAMPs) is discovered during the mPTT‐induced ICD. Meanwhile, orchestrated rhythm mPTT referring to radiotherapy procedure amplifies and balances antitumor efficiency and abundant DAMPs generation to gain optimal immune activation within clinical‐recommended hyperthermia temperature compared with conventional PTT. The in vitro and in vivo results show that the rhythm mPTT unites the killing effect and ICD induction, generating strong mPTT efficacy and active tumor‐specific adaptive immune responses. The study offers a promising strategy and a new opportunity for the clinical application of mPTT.
Glaucomatous optic neuropathy: Mitochondrial dynamics, dysfunction and protection in retinal ganglion cells
Authors: Won-Kyu Ju, Guy A. Perkins, Keun-Young Kim, Tonking Bastola, Woo-Young Choi, Soo-Ho Choi
Journal: Progress in Retinal and Eye Research (2022)

Glaucoma is a leading cause of irreversible blindness worldwide and is characterized by a slow, progressive, and multifactorial degeneration of retinal ganglion cells (RGCs) and their axons, resulting in vision loss. Despite its high prevalence in individuals 60 years of age and older, the causing factors contributing to glaucoma progression are currently not well characterized. Intraocular pressure (IOP) is the only proven treatable risk factor. However, lowering IOP is insufficient for preventing disease progression. One of the significant interests in glaucoma pathogenesis is understanding the structural and functional impairment of mitochondria in RGCs and their axons and synapses. Glaucomatous risk factors such as IOP elevation, aging, genetic variation, neuroinflammation, neurotrophic factor deprivation, and vascular dysregulation, are potential inducers for mitochondrial dysfunction in glaucoma. Because oxidative phosphorylation stress-mediated mitochondrial dysfunction is associated with structural and functional impairment of mitochondria in glaucomatous RGCs, understanding the underlying mechanisms and relationship between structural and functional alterations in mitochondria would be beneficial to developing mitochondria-related neuroprotection in RGCs and their axons and synapses against glaucomatous neurodegeneration. Here, we review the current studies focusing on mitochondrial dynamics-based structural and functional alterations in the mitochondria of glaucomatous RGCs and therapeutic strategies to protect RGCs against glaucomatous neurodegeneration.
Valvular Heart Disease: New Concepts in Pathophysiology and Therapeutic Approaches
Authors: Mackram F. Eleid, Vuyisile T. Nkomo, Sorin V. Pislaru, Bernard J. Gersh
Journal: Annual Review of Medicine (2022)

This review discusses recent advancements in the field of valvular heart disease. Topics covered include recognition of the impact of atrial fibrillation on development and assessment of valvular disease, strategies for global prevention of rheumatic heart disease, understanding and management of secondary mitral regurgitation, the updated classification of bicuspid aortic valve disease, recognition of heightened cardiovascular risk associated with moderate aortic stenosis, and a growing armamentarium of transcatheter therapies.
5-year outcomes after stereotactic ablative body radiotherapy for primary renal cell carcinoma: an individual patient data meta-analysis from IROCK (the International Radiosurgery Consortium of the Kidney)
Authors: Shankar Siva, Muhammad Ali, Rohann J M Correa, Alexander Muacevic, Lee Ponsky, Rodney J Ellis, Simon S Lo, Hiroshi Onishi, Anand Swaminath, Mark McLaughlin, Scott C Morgan, Fabio L Cury, Bin S Teh, Anand Mahadevan, Irving D Kaplan, William Chu, William Grubb, Raquibul Hannan, Michael Staehler, Andrew Warner, Alexander V Louie
Journal: The Lancet Oncology (2022)
Incident Early- and Later-Onset Type 2 Diabetes and Risk of Early- and Later-Onset Cancer: Prospective Cohort Study
Authors: Yin Zhang, Mingyang Song, Yin Cao, A. Heather Eliassen, Brian M. Wolpin, Meir J. Stampfer, Walter C. Willett, Kana Wu, Kimmie Ng, Frank B. Hu, Edward L. Giovannucci
Journal: Diabetes Care (2022)

We evaluated prospectively the association between incident early-onset (diagnosed before 40 years of age) and later-onset type 2 diabetes and early-onset (diagnosed before 50 years of age) and later-onset cancer risk.
Heterogeneity of Airway Smooth Muscle Remodeling in Asthma
Authors: Alan L. James, Graham M. Donovan, Francis H. Y. Green, Thais Mauad, Michael J. Abramson, Alvenia Cairncross, Peter B. Noble, John G. Elliot
Journal: American Journal of Respiratory and Critical Care Medicine (2022)

Rationale: Ventilatory defects in asthma are heterogeneous and may represent the distribution of airway smooth muscle (ASM) remodeling. Objectives: To determine the distribution of ASM remodeling in mild-severe asthma. Methods: The ASM area was measured in nine airway levels in three bronchial pathways in cases of nonfatal (n = 30) and fatal asthma (n = 20) and compared with control cases without asthma (n = 30). Correlations of ASM area within and between bronchial pathways were calculated. Asthma cases with 12 large and 12 small airways available (n = 42) were classified on the basis of the presence or absence of ASM remodeling (more than two SD of mean ASM area of control cases, n = 86) in the large or small airway or both. Measurements and Main Results: ASM remodeling varied widely within and between cases of nonfatal asthma and was more widespread and confluent and more marked in fatal cases. There were weak correlations of ASM between levels within the same or separate bronchial pathways; however, predictable patterns of remodeling were not observed. Using mean data, 44% of all asthma cases were classified as having no ASM remodeling in either the large or small airway despite a three- to 10-fold increase in the number of airways with ASM remodeling and 81% of asthma cases having ASM remodeling in at least one large and small airway. Conclusions: ASM remodeling is related to asthma severity but is heterogeneous within and between individuals and may contribute to the heterogeneous functional defects observed in asthma. These findings support the need for patient-specific targeting of ASM remodeling.
Zanidatamab, a novel bispecific antibody, for the treatment of locally advanced or metastatic HER2-expressing or HER2-amplified cancers: a phase 1, dose-escalation and expansion study
Authors: Funda Meric-Bernstam, Muralidhar Beeram, Erika Hamilton, Do-Youn Oh, Diana L Hanna, Yoon-Koo Kang, Elena Elimova, Jorge Chaves, Rachel Goodwin, Jeeyun Lee, Lisle Nabell, Sun Young Rha, Jose Mayordomo, Anthony El-Khoueiry, Shubham Pant, Kanwal Raghav, Jin Won Kim, Amita Patnaik, Todd Gray, Rupert Davies, Mark A Ozog, Joseph Woolery, Keun-Wook Lee
Journal: The Lancet Oncology (2022)
Determining venous thromboembolism risk in patients with adult-type diffuse glioma
Authors: Kirsten Bell Burdett, Dusten Unruh, Michael Drumm, Alicia Steffens, Jonathan Lamano, Jonathan Judkins, Margaret Schwartz, Rodrigo Javier, Christina Amidei, Eric S. Lipp, Katherine B. Peters, Albert Lai, Blaine S. C. Eldred, Amy B. Heimberger, Kathleen McCortney, Denise M. Scholtens, Craig Horbinski
Journal: Blood (2022)
Association of Estimated Glomerular Filtration Rate With Progression of Albuminuria in Individuals With Type 2 Diabetes
Authors: Ko Hanai, Tomomi Mori, Yui Yamamoto, Naoshi Yoshida, Hidekazu Murata, Tetsuya Babazono
Journal: Diabetes Care (2022)

To elucidate the association of glomerular filtration rate (GFR) at baseline with subsequent progression of albuminuria in individuals with type 2 diabetes.This was a single-center retrospective cohort study of 6,618 Japanese adults with type 2 diabetes and urinary albumin-to-creatinine ratio of <300 mg/g, comprising 2,459 women and 4,159 men with a mean (± SD) age of 60 ± 12 years. The exposure was baseline estimated GFR (eGFR) (mL/min/1.73 m2), treated as a categorical variable and classified into five categories: ≥90, 75-90, 60-75, 45-60, and <45, as well as a continuous variable. The outcome was progression of albuminuria category (i.e., from normoalbuminuria to micro- or macroalbuminuria or from micro- to macroalbuminuria). Hazard ratios (HRs) for the outcome were estimated using the multivariable Cox proportional hazards model. In the analysis treating baseline eGFR as a continuous variable, the multivariable-adjusted restricted cubic spline model was used.During the median follow-up period of 6.3 years, 1,190 individuals reached the outcome. When those with a baseline eGFR of 75-90 mL/min/1.73 m2 were considered the reference group, HRs (95% CIs) for the outcome in those with a baseline eGFR of ≥90, 60-75, 45-60, or <45 mL/min/1.73 m2 were 1.38 (1.14-1.66), 1.34 (1.14-1.58), 1.81 (1.50-2.20), or 2.37 (1.84-3.05), respectively. Furthermore, the inverse J-shaped curve was more clearly shown by the spline model.This study of Japanese adults with type 2 diabetes suggests that both high and low GFRs are implicated in the pathogenesis of albuminuria progression.
A randomized, placebo-controlled phase 3 trial of the PI3Kδ inhibitor leniolisib for activated PI3Kδ syndrome
Authors: V. Koneti Rao, Sharon Webster, Anna Šedivá, Alessandro Plebani, Catharina Schuetz, Anna Shcherbina, Niall Conlon, Tanya Coulter, Virgil A. Dalm, Antonino Trizzino, Yulia Zharankova, Elaine Kulm, Julia Körholz, Vassilios Lougaris, Yulia Rodina, Kath Radford, Jason Bradt, Klaus Kucher, Anurag Relan, Steven M. Holland, Michael J. Lenardo, Gulbu Uzel
Journal: Blood (2022)

Abstract Activated phosphoinositide 3-kinase delta (PI3Kδ) syndrome (APDS) is an inborn error of immunity with clinical manifestations including infections, lymphoproliferation, autoimmunity, enteropathy, bronchiectasis, increased risk of lymphoma, and early mortality. Hyperactive PI3Kδ signaling causes APDS and is selectively targeted with leniolisib, an oral, small molecule inhibitor of PI3Kδ. Here, 31 patients with APDS aged ≥12 years were enrolled in a global, phase 3, triple-blinded trial and randomized 2:1 to receive 70 mg leniolisib or placebo twice daily for 12 weeks. Coprimary outcomes were differences from baseline in the index lymph node size and the percentage of naïve B cells in peripheral blood, assessed as proxies for immune dysregulation and deficiency. Both primary outcomes were met: the difference in the adjusted mean change (95% confidence interval [CI]) between leniolisib and placebo for lymph node size was −0.25 (−0.38, −0.12; P = .0006; N = 26) and for percentage of naïve B cells, was 37.30 (24.06, 50.54; P = .0002; N = 13). Leniolisib reduced spleen volume compared with placebo (adjusted mean difference in 3-dimensional volume [cm3], −186; 95% CI, −297 to −76.2; P = .0020) and improved key immune cell subsets. Fewer patients receiving leniolisib reported study treatment-related adverse events (AEs; mostly grades 1-2) than those receiving placebo (23.8% vs 30.0%). Overall, leniolisib was well tolerated and significant improvement over placebo was notable in the coprimary endpoints, reducing lymphadenopathy and increasing the percentage of naïve B cells, reflecting a favorable impact on the immune dysregulation and deficiency seen in patients with APDS. This trial was registered at www.clinicaltrials.gov as #NCT02435173.
North American Blastic Plasmacytoid Dendritic Cell Neoplasm Consortium: position on standards of care and areas of need
Authors: Naveen Pemmaraju, Hagop Kantarjian, Kendra Sweet, Eunice Wang, Jayastu Senapati, Nathaniel R. Wilson, Marina Konopleva, Arthur E. Frankel, Vikas Gupta, Ruben Mesa, Matthew Ulrickson, Edward Gorak, Sumeet Bhatia, Tulin Budak-Alpdogan, James Mason, Maria Teresa Garcia-Romero, Norma Lopez-Santiago, Gabriela Cesarman-Maus, Pankit Vachhani, Sangmin Lee, Vijaya Raj Bhatt, William Blum, Roland B. Walter, Dale Bixby, Ivana Gojo, Madeleine Duvic, Raajit K. Rampal, Marcos de Lima, James Foran, Amir T. Fathi, Aric Cameron Hall, Meagan A. Jacoby, Jeffrey Lancet, Gabriel Mannis, Anthony S. Stein, Alice Mims, David Rizzieri, Rebecca Olin, Alexander Perl, Gary Schiller, Paul Shami, Richard M. Stone, Stephen Strickland, Matthew J. Wieduwilt, Naval Daver, Farhad Ravandi, Sumithira Vasu, Monica Guzman, Gail J. Roboz, Joseph Khoury, Muzaffar Qazilbash, Phyu P. Aung, Branko Cuglievan, Yazan Madanat, Mohamed A. Kharfan-Dabaja, Anna Pawlowska, Justin Taylor, Martin Tallman, Prajwal Dhakal, Andrew A. Lane
Journal: Blood (2022)
Molecular classification and biomarkers of clinical outcome in breast ductal carcinoma in situ: Analysis of TBCRC 038 and RAHBT cohorts
Authors: Siri H. Strand, Belén Rivero-Gutiérrez, Kathleen E. Houlahan, Jose A. Seoane, Lorraine M. King, Tyler Risom, Lunden A. Simpson, Sujay Vennam, Aziz Khan, Luis Cisneros, Timothy Hardman, Bryan Harmon, Fergus Couch, Kristalyn Gallagher, Mark Kilgore, Shi Wei, Angela DeMichele, Tari King, Priscilla F. McAuliffe, Julie Nangia, Joanna Lee, Jennifer Tseng, Anna Maria Storniolo, Alastair M. Thompson, Gaorav P. Gupta, Robyn Burns, Deborah J. Veis, Katherine DeSchryver, Chunfang Zhu, Magdalena Matusiak, Jason Wang, Shirley X. Zhu, Jen Tappenden, Daisy Yi Ding, Dadong Zhang, Jingqin Luo, Shu Jiang, Sushama Varma, Lauren Anderson, Cody Straub, Sucheta Srivastava, Christina Curtis, Rob Tibshirani, Robert Michael Angelo, Allison Hall, Kouros Owzar, Kornelia Polyak, Carlo Maley, Jeffrey R. Marks, Graham A. Colditz, E. Shelley Hwang, Robert B. West
Journal: Cancer Cell (2022)
Evaluation of cell-free DNA approaches for multi-cancer early detection
Authors: Arash Jamshidi, Minetta C. Liu, Eric A. Klein, Oliver Venn, Earl Hubbell, John F. Beausang, Samuel Gross, Collin Melton, Alexander P. Fields, Qinwen Liu, Nan Zhang, Eric T. Fung, Kathryn N. Kurtzman, Hamed Amini, Craig Betts, Daniel Civello, Peter Freese, Robert Calef, Konstantin Davydov, Saniya Fayzullina, Chenlu Hou, Roger Jiang, Byoungsok Jung, Susan Tang, Vasiliki Demas, Joshua Newman, Onur Sakarya, Eric Scott, Archana Shenoy, Seyedmehdi Shojaee, Kristan K. Steffen, Virgil Nicula, Tom C. Chien, Siddhartha Bagaria, Nathan Hunkapiller, Mohini Desai, Zhao Dong, Donald A. Richards, Timothy J. Yeatman, Allen L. Cohn, David D. Thiel, Donald A. Berry, Mohan K. Tummala, Kristi McIntyre, Mikkael A. Sekeres, Alan Bryce, Alexander M. Aravanis, Michael V. Seiden, Charles Swanton
Journal: Cancer Cell (2022)

In the Circulating Cell-free Genome Atlas (NCT02889978) substudy 1, we evaluate several approaches for a circulating cell-free DNA (cfDNA)-based multi-cancer early detection (MCED) test by defining clinical limit of detection (LOD) based on circulating tumor allele fraction (cTAF), enabling performance comparisons. Among 10 machine-learning classifiers trained on the same samples and independently validated, when evaluated at 98% specificity, those using whole-genome (WG) methylation, single nucleotide variants with paired white blood cell background removal, and combined scores from classifiers evaluated in this study show the highest cancer signal detection sensitivities. Compared with clinical stage and tumor type, cTAF is a more significant predictor of classifier performance and may more closely reflect tumor biology. Clinical LODs mirror relative sensitivities for all approaches. The WG methylation feature best predicts cancer signal origin. WG methylation is the most promising technology for MCED and informs development of a targeted methylation MCED test.
Bile acids and neurological disease
Authors: Michael J. Hurley, Rachel Bates, Jane Macnaughtan, Anthony H.V. Schapira
Journal: Pharmacology & Therapeutics (2022)

This review will focus on how bile acids are being used in clinical trials to treat neurological diseases due to their central involvement with the gut-liver-brain axis and their physiological and pathophysiological roles in both normal brain function and multiple neurological diseases. The synthesis of primary and secondary bile acids species and how the regulation of the bile acid pool may differ between the gut and brain is discussed. The expression of several bile acid receptors in brain and their currently known functions along with the tools available to manipulate them pharmacologically are examined, together with discussion of the interaction of bile acids with the gut microbiome and their lesser-known effects upon brain glucose and lipid metabolism. How dysregulation of the gut microbiome, aging and sex differences may lead to disruption of bile acid signalling and possible causal roles in a number of neurological disorders are also considered. Finally, we discuss how pharmacological treatments targeting bile acid receptors are currently being tested in an array of clinical trials for several different neurodegenerative diseases.